Phenanthrene derivatives

ABSTRACT

The present invention relates to compounds of formula (I) ArCH2R1 (I) or a monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a phenanthrene or substituted phenanthrene ring system; R1 contains not more than eight carbon atoms and is a group   &lt;IMAGE&gt;   wherein m is 0 or 1; R5 is hydrogen; R6 and R7 are the same or different and each is hydrogen or C1-3 alkyl optionally substituted by hydroxy; R8 and R9 are the same or different and each is hydrogen or C1-3 alkyl; &lt;IMAGE&gt;   is a five-or six-membered saturated carbocyclic ring; R10 is hydrogen, methyl or hydroxymethyl; R11, R12 and R13 are the same or different and each is hydrogen or methyl; R14 is hydrogen, methyl, hydroxy, or hydroxymethyl.

This is a divisional of co-pending application Ser. No. 659,268 filed onOct. 10, 1984 now U.S. Pat. No. 4,719,055 which is a continuation inpart of Ser. No. 499,865 filed June 1, 1983 now abandoned.

The present invention relates to polycyclic aromatic alkanol derivativeswhich have been found to have biocidal activity. More specifically theinvention concerns aminoalkanol derivatives containing a polycarbocyclicaromatic ring system, methods for the synthesis thereof, pharmaceuticalformulations thereof, novel intermediates therefor, pharmaceuticalformulations thereof and the use thereof as biocidal agents,particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I)including these ethers may contain no more than 30 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof;

wherein Ar is a phenanthrene ring optionally substituted by one, two, orthree substituents (the substituents will contain not more than fourcarbon atoms in total when taken together being the same or differentand are selected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, eachoptionally substituted by hydroxy or C₁₋₂ alkoxy; halogen substitutedC₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer0,1 or 2 and R² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂alkoxy; or the phenanthrene ring is optionally substituted by a groupNR³ R⁴ containing not more than 5 carbon atoms wherein R³ and R⁴ are thesame or different and each is a C₁₋₃ alkyl group or NR³ R⁴ forms a five-or six-membered heterocyclic ring optionally containing one or twoadditional heteroatoms);

R¹ contains not more than eight carbon atoms and is a group ##STR3##wherein M is 0 or 1; R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₃ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;##STR4## is a five- or six-membered saturated carbocyclic ring; R¹⁰ ishydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains notmore than 28 carbon atoms in total.

Ar is suitably 9-phenanthrenyl, ##STR5## suitably m is 0, suitably R¹ is##STR6## wherein R¹⁶ is CH₂ OH,CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH,

R¹⁸ is hydrogen or methyl.

Preferably R¹⁶ is CH₂ OH or CH(CH₃)OH; R¹⁷ is hydrogen, methyl, ethyl orCH₂ OH.

Most preferably R¹ is a diol of the structure ##STR7## wherein R¹⁹ ishydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferablymethyl.

Acid addition salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful acid addition salts of thecompounds of the formula (I) are useful intermediates in the preparationand purification of compounds of the formula (I) and pharmaceuticallyuseful acid addition salts thereof, and are therefore within the scopeof the present invention. Thus, acid addition salts of the compounds ofthe formula (I) useful in the present invention include but are notlimited to those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, and organic acids such asisethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine.

Acid addition salts particularly useful as biocidal agents are thosethat are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic lactic,citric and isethionic acids.

The preferred pharmacologically and pharmaceutically acceptable acidaddition salts are those that are soluble in solvents suitable forparenteral administration, for example, hydrochlorides,methanesulfonates and isethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2-Methyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol,

2-Methyl-2-((4-phenanthrenylmethyl)amino)-1,3-propanediol,

2-Methyl-2-((2-phenanthrenylmethyl)amino)-1,3-propanediol,

2-Methyl-2-((3-phenanthrenylmethyl)amino)-1,3-propanediol,

(+-)(2R*,3S*)-2-((9-Phenanthrenylmethyl)amino)-2-methyl-1,3-butanediol,

2-Ethoxymethyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol,

2-(((10-Ethoxy-9-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol,

3-Methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol,

2-(((9-Ethoxy-1-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol,

2-Methyl-2-((9-phenanthrenylmethyl)amino)-1,4-butanediol,

2-Isopropyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol

(1α,2β,3α)-2-((9-Phenanthrenylmethyl)amino)-1,3-cyclohexanediol andethers, esters; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the mostpreferred compound is2-((9-phenanthrenylmethyl)amino)-2-methyl-1,3-propanediol, and ethers,esters; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters, and salts thereofmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure. Thus, the compounds of formula (I)may, for example, be prepared by any of the methods defined below.

1. The reduction of a compound of formula (II) ##STR8## Wherein R¹ -R⁴are as hereinbefore defined or an appropriately protected derivativethereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalent reagentas outlined by J. March, Advanced Organic Chemistry, 2nd ed., pages819-820, McGraw Hill, New York, 1977. The reduction is suitably carriedout with the compound of formula (II) in solution in an inert solvent ormixture of solvents compatible with the reducing agent, at a non-extremetemperature, for example, between 0° and 80° C., conveniently at roomtemperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2-dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for examplediethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R. Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) optionally inthe presence of an acid (for example glacial acetic acid or ethanolichydrochloric acid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR9## wherein Ar and R¹ -R⁴ are as defined in (I)except that R⁵ =H, and reduce the compound of the formula (II) so formedin situ. The reaction of the compounds of the formulae (III) and (IV) isagain suitably carried out using conditions and reagents which are wellknown to those skilled in the art, for example in the presence of anacid, such as a sulfonic acid, i.e. P-toluenesulfonic acid, in anappropriate inert solvent, such as an aromatic hydrocarbon, for suitablytoluene, with azeotropic removal of water followed by treatment with thereducing agent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cycanoborohydride.

The compound of formula (III) may be in the form of a protectedaldehyde, for example an acetal, which liberates the aldehyde functionunder the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate polycyclic aromatic hydrocarbon with a formylating agentsuch as that generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ orequivalent reagents, for example, according to the method of A. Reicheet al., Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Kochreaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction (HCN/HCl/ZnCl₂),and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO or POCl₃ /Me₂ NCHO) (J.March, vide supra pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate polycyclic aromatic hydrocarbon substituted by a suitablefunctional group such as CH₂ OH, CHBr₂, CH₃, COCH₃, COOH, or CN, andconverting this functional group to an aldehyde group by methods wellknown to those skilled in the art.

Where the polycyclic aromatic ring bears substituents, the compound offormfula (III) may be prepared by a variety of methods known in the artof organic chemistry depending on the nature of the substituent on thepolycyclic ring. For example, if the substituent(s) is a halogen, thestarting materials may be prepared by direct treatment of the polycyclicaromatic hydrocarbon with a halogenating agent (e.g. Cl₂, Br₂, or SO₂Cl₂) or indirectly by such routes as the sandmeyer reaction (H. H.Hodgson, Chem Rev. 40, 251 (1947). If the substituent(s) is alkyl, thepolycyclic aromatic hydrocarbon may be reacted with the appropriatereagents under Friedel-Crafts reaction conditions (G. A. Olah, FriedelCrafts and Related Reactions, Vols. 1-3, Interscience, New York, NY,1963-1965).

The compounds of the formula (IV) also may be prepared by methods knownin the art, for example, by the reaction of compound NO₂ CH₂ R² with anappropriate aldehyde, conveniently acetaldehyde or formaldehyde (as inB. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940)) followedby reduction (as outlined in J. March, vide supra, pages 1125-1126),conveniently by hydrogen and a metal catalyst (for example, a platinumcontaining catalyst) in an appropriate solvent, conveniently glacialacetic acid.

2. The reduction of a compound of the formula (V) ##STR10## wherein Arand R¹ -R⁴ are as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra, page 1122), for example, a hydride reagent such aslithium aluminium hydride in an inert solvent, such as an ether, i.e.tetrahydrofuran, at a non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.

The compound of the formula (V) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereofas outlined in J. March, vide supra, pages 382-390) for example, an acidhalide in an inert solvent, with an amine of the formula (IV) in whichthe hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (V) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbeforedefined and L is a leaving group), with a compound of the formula (IV)as hereinbefore defined. Suitable leaving groups are those defined by J.March, vide supra pages 325-331, and include halogens such as chlorineor bromine and sulfonic acid derivatives such as p-toluenesulfonate. Thereaction is suitably carried out in an appropriate solvent, such as adipolar aprotic solvent or alcohol at a non-extreme temperature, forexample 50°-100°. The compounds of the formula ArCH₂ L can be preparedby methods well known to those skilled in the art.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particularthose methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g. are toxicto certain living cells which are detrimental to mammals, for examplepathogenic organisms and tumor cells.

This toxicity to pathogenic organisms has been demonstrated by activityagainst viruses (e.g. Herpes simplex 1/vero), fungi (e.g. Candidaalbicans), protozoa (e.g. Eimeria tenella and Trichomonas vaginalis),bacteria (e.g. Mycoplasma smegmatis and Streptococcus pyogenes), andhelminths (e.g. Nippostrongylus brasiliensis and Brugia pahangi). Theantitumor activity of compounds of formula (I) has been demonstrated ina number of recognized screens and primarily by activity against asciticP388/0 leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumours) and consequent increase in survivalduration as compared to an untreated tumor bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated control tumorbearing animals. Compounds of formula (I) are active against murinetumors such as lymphocytic leukemia P388/0, lymphocytic leukemia L1210,melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al. in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumorsusing the procedure for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknowwn primary, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. (As used herein "cancer" is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted.)This is a procedure in which the prevention of tumor cell colonyformation, i.e. tumor cell replication, by a drug has been shown tocorrelate with clinical antitumor activity in man (D. D. Von Hoff etal., Cancer Chemotherapy and Pharmacology 6, 265 (1980); S. Salmon andD. D. Von Hoff, Seminars in Oncology, 8, 377 (1981)).

Compounds of formula I which have been found to have antitumor activityintercalate in vitro with DNA (this property is determined byviscometric methods using the procedure of W. D. Wilson et al., NucleicAcids Research 4, 2697 (1954)) and a log P as calculated by the methodof C. Hansch and A. Leo in Substituent Constants for CorrelationAnalysis in Chemistry and Biology, John Wiley and Sons, New York, 1979,lying in the range between -2.0 and +2.5.

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, andnature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day or byintravenous infusion for selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula I given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be administeredalone, it is preferable to present the active compound in apharamaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefore.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I) an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefore.

While the antitumor activity of the compounds of formula (I) is believedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration.Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsaline and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parenteraladministration as above.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

General Comments

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3 Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"silica gel (Merck & Co., Inc., Merck Chemical Division, Rahway, NJ,07065 silica gel 60, 30-400 mesh). In this procedure an appropriatevolume sintered glass funnel was filled approximately 3/4 full with theSiO₂ and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gentle suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR, MS data of all new products were consistent withthe expected and proposed structures. The positions assigned tostructural isomers were unequivocally determined by a number of NMRtechniques. All final products were dried in a vacuum oven at 20 mm Hgpressure at the temperature indicated overnight (12-16 h). Alltemperatures are in degrees Celsius. Other abbreviations that were used:room temperature (RT), absolute (abs.), round bottom flask (RB flask),minutes (min), hours (h).

EXAMPLE 1 2-Methyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride

To a 2 L Erlenmeyer flask was added 9-phenanthrenecarbaldehyde (AldrichChemical Co., Milwaukee, WI, 53201, 20.63 g, 0.1 mol),2-methyl-2-amino-1,3-propanediol (Aldrich, 9.13 g, 86.8 mmol),p-toluenesulfonic acid.H₂ O (Eastman Kodak Co., Rochester, NY, 14650,0.1 g, 0.5 mmol), and PhCH₃ (500 mL). The mixture was warmed to refluxfor a few minutes and H₂ O (2-3 mL) was driven off. The resulting goldencolored solution was allowed to cool to RT, diluted with absolute EtOH(500 mL) and stirred overnight. NaBH₃ CN (Aldrich, 95%, 4.40 g, 70 mmol)was added to the reaction. After the NaBH₃ CN dissolved, an indicator(bromocresol green, Eastman, 5 mg) was added. To the resulting bluesolution was added 5 drops of 1M solution of HCl gas in absolute EtOHevery 15 minutes. After 3 days the indicator turned green then yellowand voluminous white precipitate was present in the flask. To the flaskwas then added 1M HCl gas (10 mL) in absolute EtOH. The reaction wasdiluted to 4 L with absolute ether and stirred for 1 h. The precipitatewas then collected by filtration using a medium porosity glass frittedfunnel and pressed dry. The filter cake was washed thoroughly with CH₂Cl₂ (4×500 mL), pressed, sucked dry, and dried overnight (100°).Recrystallization from EtOH/Et₂ O (3x) gave 11.84 g (36%) of2-methyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol hydrochloridemp 144°-146°, (C, H, Cl, N).

EXAMPLE 2 2-Methyl-2-((2-phenanthrenylmethyl)amino)-1,3-propanediol

2A. 2-Phenanthrenecarbaldehyde

2-Acetylphenanthrene (Aldrich) was converted to the corresponding acidby the method of E. Mosettig and J. van de Kamp, J. Amer. Chem. Soc. 523704, (1930). The acid was then converted to the corresponding acidchloride by the method of E. Mosettig and J. van de Kamp, J. Amer. Chem.Soc. 55, 2995 (1933).

To a solution of the crude acid chloride (10.66 g, 45 mmol) in 250 mL ofacetone (degassed with N₂) was added Cu(PPh₃)₂ BH₄ (Fluka ChemicalCorp., 255 Oser Ave., Hauppauge, NY, 11787, 27.1 g, 45 mmol) as a solid.The reaction mixture was then stirred overnight. The reaction was thenfiltered, and the solvent removed by rotary evaporation. Furtherinorganic material was removed by partially dissolving the solid in dryPhCH₃ and filtration. The PhCH₃ was subsequently removed by rotaryevaporation. The solid bisulfite complex of the aldehyde was formed byadding satd. NaHSO₃ (150 mL) to the aldehyde and stirring vigorously for5 h. The complex was removed by filtration and digested in 1N NaOH. Themixture was extracted once with Et₂ O (1 L). The organic layer was dried(MgSO₄), filtered, and the solvent removed to give the crude aldehydewhich was purified by preparative HPLC using PhCH₃ as the elutingsolvent to give pure 2 -phenanthrenecarbaldehyde (5.1 g, 25%) mp 58°-60°(lit. 59°-59.5°, E. Mosettig and J. van de Kamp, J. Amer. Chem. Soc. 552395 (1933)), (C, H).

2B. 2-Methyl-2-((2-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1,2-phenanthrenecarbaldehyde and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 2-methyl-2-((2-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride mp 243°-245°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 32-(((10-Ethoxy-9-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol

3A. 9-Ethoxy-1-phenanthrenecarbaldehyde

3B. 10-Ethoxy-9-phenanthrenecarbaldehyde

3C. 9-Ethoxy-3-phenanthrenecarbaldehyde

9-Ethoxyphenanthrene (Cambridge Chemical, Inc., 202 E. Smith St.,Milwaukee, WI, 53207, 25 g, 0.113 mol) was formylated using theprocedure of A. Rieche et al. (Chem Ber. 93, 88 (1960). The crudealdehyde was chromatographed on a plug of SiO₂, followed by preparativeHPLC using PhCH₃ as the eluting solvent. Three purified isomers wereobtained as described below:

3A. 9-Ethoxy-1-phenanthrenecarbaldehyde, 3.24 g (11%), (C, H), (Rf=0.55,SiO₂, PhCH₃), mp 79°-82°.

3B. 10-Ethoxy-9-phenanthrenecarbaldehyde, 15.0 g (60%), (C, H),(Rf=0.50, SiO₂, PhCH₃), mp 67°-70°.

3C. 9-Ethoxy-3-phenanthrenecarbaldehyde, 2.57 g (9%), (C, H), (Rf=0.35,SiO₂, PhCH₃), mp 140°-141°.

3D.2-(((10-Ethoxy-9-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1,10-ethoxy-9-phenanthrene carbaldehyde (3B) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave2-(((10-ethoxy-9-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 199°-200°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 42-(((9-Ethoxy-1-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol

Using the reductive amination procedure outlined in 1,9-ethoxy-1-phenanthrenecarbaldehyde and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave2-(((9-ethoxy-1-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediolhydrochloride mp 215°-216.5° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 5 2-Methyl-2-((4-phenanthrenylmethyl)amino)-1,3-propanediol

5A. Phenanthrene-4-carbaldehyde

4-Phenanthrenemethanol (Aldrich, 29 g, 0.14 mol) was treated withpyridinium chlorochromate (PCC) (Aldrich, 45 g, 0.21 mol) in CH₂ Cl₂(2000 mL). After 6 h at RT, the reaction mixture was filtered through aplug of SiO₂ to give after removal of solvent and drying andcrystallization from CH₃ OH, 20.5 g (71%) ofphenanthrene-4-carboxaldehyde mp 82.5°-84.5° (C, H).

5B. 2-Methyl-2-((4-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in 1,phenanthrene-4-carbaldehyde (5A) and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 2-methyl-2-((4-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride mp 198°-200° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 6 2-Methyl-2-((3-phenanthrenylmethyl)amino)-1,3-propanediol

6A. Phenanthrene-3-carboxaldehyde

Using the procedure outlined in 2A for 2-acetylphenanthrene,3-acetylphenanthrene (Aldrich, technical grade), 25 g, 0.114 mol) gave13 g (51%) of phenanthrene-3-carboxylic acid. 15.6 g (0.07 mol) of thisacid was converted to the corresponding acid chloride, then to 8.37 g(58%) of phenanthrene-3-carboxaldehyde mp 78°-80° (lit. 79.5°-80°, E.Mosettig and J. van de Kamp, J. Amer. Chem. Soc. 55 2395 (1933)), (C,H).

6B. 2-Methyl-2-((3-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride

Using the reductive amination outlined in 1, phenanthrene-3-carbaldehyde(6A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-methyl-2-((3-phenanthrenylmethyl)amino)-1,3-propanediol hydrochloridemp 209°-211°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 7(+-)(2R*,3S*)-2-(9-Phenanthrenylmethyl)amino)-2-methyl-1,3-butanediol

7A. (+-)(2R*,3S*)-2-Methyl-2-nitro-1,3-butanediol and

7B. (+-)(2R*,3R*)-2-Methyl-2-nitro-1,3-butanediol

To a mixture of 2-nitro-1-propanol (Aldrich, 63.0 g, 0.60 mol) andacetaldehyde (Eastman, 39.6 g, 0.90 mol) cooled in an ice bath under N₂was added cold H₂ O (40 mL) and calcium hydroxide (200 mg). The mixturewas allowed to warm to RT over 2 h and then stirred for 68 h. Theresulting solution was neutralized with excess solid CO₂. The mixturewas stirred for 1 h before filtration through a Millipore filter(Millipore Corp., Bedford, MA, 01730). The filtrate was thenconcentrated under vacuum at 35°. The residue, a viscous syrup whichpartially crystallized on drying under vacuum (0.1 mm, RT, 48 h), wastriturated with cold Et₂ O (35 mL). Solid white crystals which formedwere collected by filtration, washed with cold Et₂ O (3×15 mL) and driedunder vacuum (0.1 mm, RT) to give 34.1 g of material, judged by NMR tobe (+- )(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol 7A (purity >97%,racemic). After recrystallization, the diastereoiomeric purity was >99%,mp 78.5°-81° (lit. 78°; cf. Beil 1, 482 in Henry, Bull. Soc. Chim. Fr.[3] 15, 1224), (C, H, N).

The original filtrate (including wash) was concentrated under vacuum toa pale yellow liquid which was subjected to flash chromatography asfollows: The sample was mixed with hexane:EtOAc (2:1, 100 mL) and addedto a column of dry SiO₂ (1.5 kg). The column was eluted withhexane:EtOAc (2:1, 12 L) then hexane:EtOAc (1:1, 6 L) while 500 mLfractions were collected. Appropriate fractions were combined. Pureproduct was found in the final 8 L; yield, 38.7 g of viscous syrup,judged by NMR to be a 1:1 mixture of the two racemic diastereomers (7Aand 7B), (C, H, N).

This and another batch of the 1:1 diasteriomeric mixture (prepared asdescribed above) were combined (67 g, total) and subjected to successiveliquid-liquid partitioning between H₂ O and EtOAc to give pure samples(99% on the basis of NMR and HPLC (Hamilton PRP-1 column using 3.5%aqueous acetonitrile as the mobile phase)) of(+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (7A) (24.9 g, k'=4.3, C,H, N) and (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (7B) (15.8 g,k'=2.1, C, H, N, a colorless, viscous liquid).

7C. (+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane and

7D. (+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane

The relative configurations of these two diasteriomeric pairs (7A and7B) were unequivocably assigned on the basis of comparative NMR analysisof the respective cyclic acetals derived from benzaldehyde. Thus, 7A(1.49 g, 0.01 mol) and benzaldehyde (Mallinckrodt, 1.06 g, 0.01 mol)were condensed in benzene in the presence of a catalytic amount ofp-toluenesulfonic acid with azeotropic removal of water (according tothe method of H. Piotrowska, B. Serafin and T. Urbanski, Tetrahedron109, 379 (1963)). After successive washing with satd. NaHCO₃ solution,drying (MgSO₄), filtration, and removal of the benzene by rotaryevaporation, a pale yellow solid was obtained. A solution of thisproduct in ethanol at 0° C. provided an oil which was isolated bydecanting the mother liquor and drying under vacuum (0.1 mm, RT). Theyield was 1.48 g (62%) of(+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (7C) (C, H,N).

Similarly prepared from 7B and benzaldehyde was(+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (7D) (74%)(C, H, N).

7E. (+-)(2R*,3R*)-2-Amino-2-methyl-1,3-butanediol acetate

To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (7B,22.1, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parrapparatus at 50 psi of H₂ during a 48 h period at RT. The catalyst wasremoved by filtration through a Millipore® filter, and the solventremoved under vacuum (2 days). The viscous, colorless syrup wasdissolved in abs. EtOH (30 mL). Dilution with abs. Et₂ O (300 mL) gave acloudy liquid which was placed in a refrigerator for two days. Duringthis time, colorless crystals formed. They were washed with Et₂ O anddried in a vacuum oven at RT for two days. The yield of(+-)(2R*,3R*)-2-amino-methyl-1,3-butanol acetate was 25.6 g (97%) mp117°-121°, (C, H, N).

7F. (+-)(2R*,3S*)-2-Amino-2-methyl-1,3-butanediol acetate

Prepared from (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (7A) asdescribed for 7E (93%) (C, H, N) mp 163°-165° C.

7G.(+-)(2R*,3S*)-2-((9-Phenanthrenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride

To a RB flask was added (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediolacetate (7F) and an equimolar amount of NaOCH₃ and CH₃ OH (100 mL).After warming, the solvent was removed by rotary evaporation, and afteraddition of phenanthrene-9-carbaldehyde (Aldrich), the reaction runfollowing the reductive amination procedure outlined in 1 to give(2R*,3S*)-2-((9-phenanthrenylmethyl)amino)-2-methyl-1,3-butanediolhydrochloride mp 204°-206° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 82-Ethoxymethyl-2-((9-Phenanthrenylmethyl)amino)-1,3-propanediol

8A. 3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 34.0g, 0.85 mol) was washed with dry hexane to remove the oil and suspendedin dry DMF (300 mL). To the mixture was added a solution of3,5-diphenyl-1H,3H,5H-oxazolo(3,4-c)oxazole-7a(7H)-methanol (208.2 g,0.7 mol, prepared by the method of J. Pierce et al., J. Amer. Chem. Soc.73 2595 (1951)) in dry DMF (300 mL) keeping the reaction mixture between30°-35°. The salt suspension was stirred at RT for 60 min, diluted withdry DMF (200 mL) to facilitate stirring, cooled, then treated with ethyliodide (Aldrich, excess) at such a rate that the reaction temperaturewas between 20°-35°. The mixture was stirred at RT for 2 h, thencautiously treated with absolute EtOH (30 mL). The resulting mixture wasdiluted with Et₂ O (2.5 L) and the resulting solids removed byfiltration. The solvent was then removed using a rotary evaporator togive 229.5 g of a yellow oil containing both starting material anddesired product. A solution of the oil in chloroform was mixed with SiO₂(200 g) and the solvent removed. The solid was then added to a column ofSiO₂ (800 g). Elution with the EtOAc/hexane (1:3.5) gave 139.7 g (61.3%)of 3,5-diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole. Ananalytical sample was obtained by recrystallization from hexane, mp83.5°-85.°, (C, H, N). The bulk of the material was used without furtherpurification.

8B. 2-Amino-2-ethoxymethyl-1,3-propanediol hydrochloride1/4H₂ O

3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole (8A, 136g, 0.42 mol) was dissolved in 6N HCl (400 mL) and the resulting solutionstirred 1.5 h at RT. After extraction with Et₂ O (2×200 mL) to removebenzaldehyde, the aqueous solution was concentrated on a rotaryevaporator to give a colorless oil. This was cooled in an ice bath tofacilitate crystallization. The solid which formed was slurried withcold CH₃ CN, filtered, then washed with Et₂ O and dried in a vacuum ovenat RT to give 71 g (89%) of 2-amino-2-ethoxymethyl-1,3-propanediolhydrochloride.1/4H₂ O mp 78°-79°, (C, H, Cl, N).

8C. 2-Ethoxymethyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined for 7G,phenanthrene-9-carbaldehyde (Aldrich) and2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H₂ O (8B) gave2-ethoxymethyl-2-(((9-phenanthrenyl)methyl)amino)-1,3-propanediolhydrochloride mp 173°-175°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 9 3-Methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol

9A. 4-Aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane

A solution of 2-amino-2-methyl-1,3-propanediol (Aldrich, 303.4 g, 3.0mol), cyclohexanone (Fisher, 294.5 g, 3.0 mol) and PhCH₃ (400 mL) wasrefluxed for approximately 2 h with azeotropic removal of H₂ O. Thematerial which crystallized from the PhCH₃ on cooling was recrystallizedtwice from hexane to give 444.4 g of4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro(4.5]decane (80%) mp 52°-54°,(C, H, N).

9B. 4-Aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 75 g,1.9 mol) was washed with dry hexane to remove the oil and suspended indry DMF (200 mL). To the mixture was added a solution of4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane (27.8 g, 1.5 mol)in dry DMF (200 mL) keeping the reaction mixture temperature between30°-35°. Small amounts of DMF were added as necessary to facilitatestirring. The mixture was stirred at RT for 1.5 h, then cooled andtreated with methyl iodide (Fisher, 234.2 g, 102.7 mL, 1.65 mol) keepingthe reaction temperature between 20°-30°. The mixture was stirred 2 h atRT and slowly treated with absolute EtOH (40 mL), then diluted with dryEt₂ O (3 L). The reaction mixture was filtered and the solvent removedby rotary evaporation. The residue was then fractionally distilled togive 209.7 g (70.3%) of4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane as a colorlessliquid bp 114°/14 mm, (C, H, N).

9C. 2-Amino-3-methoxy-2-methyl-1-propanol

A solution of 4-aza-3-methoxymethyl-3-methyl-1-oxaspiro(4.5)decane (9B,299 g, 1.5 mol) and 6N HCl (500 mL) was refluxed for 60 min. On cooling,two layers formed, the upper one containing cyclohexanone was removed byextraction with Et₂ O (2×400 mL). The lower aqueous layer wasconcentrated on a rotary evaporator to give a syrup which then wastreated with excess 50% NaOH. The resulting slurry was extracted withEt₂ O/CH₂ Cl₂ (2:1, 4×500 mL), then with CH₂ Cl₂ (500 mL). The solventwas removed by rotary evaporation to give 198 g of pale oil. Fractionaldistillation of this oil gave 166 g (93%) of2-amino-3-methoxymethyl-1-propanol as a colorless oil, bp 94° C./17 mm,(C, H, N).

9D. 3-Methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanolhydrochloride

Using the reductive amination procedure outlined in 7G,phenanthrene-9-carbaldehyde (Aldrich) and2-amino-3-methoxy-2-methyl-1-propanol (9C) gave3-methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanolhydrochloride mp 211°-213° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 10 2-Methyl-2-((9-Phenanthrenylmethyl)amino)-1,4-butanediol

10A. Ethyl N-benzylidene-1-alaninate

Ethyl N-benzylidene-1-alaninate was prepared according to the generalprocedure of G. Stork et al., J. Org. Chem. 41, 349 (1976), bp98°-100°/0.4 mm (lit. 100°/0.3 mm, A. Calcagni et al., Synthesis 445(1981))

10B. 2-(2-Iodoethoxy)tetrahydro-2-H-pyran

Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was addeddropwise to a cooled solution of iodoethanol (Aldrich, 98 g, 0.57 mol)in Et₂ O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). Thesolution was then stirred for 1 h at 5°. Solid K₂ CO₃ (Mallinckrodt, 5g) was then added to the reaction mixture and the resulting suspensionstirred an additional 1 h at RT. The reaction was then filtered and theremaining solid washed with Et₂ O (1 L). The organic solutions werecombined and concentrated on a rotary evaporator (in a flask washed with1% NEt₃ in H₂ O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (100 g,68.9%) was used without further purification.

10C. Ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate

A solution of lithium diisopropylamide was prepared by dropwise additionof n-BuLi (Aldrich, 1.6M in hexane, 228 mL, 0.365 mol) to a solution ofdiisopropylamine (Aldrich, 51.6 g, 0.51 mol) in a mixture of dry THF(700 mL) and dry HMPA (Aldrich, 40 mL) kept at 30°-40°. The solution wasthen cooled to -70° and a solution of ethyl N-benzylidene-1-alaninate(10A, 74.9 g, 0.365 mol) was added dropwise to the solution allowing thereaction mixture warm to -20° for several min. The resulting redsolution was then cooled to -70°. (2-Iodoethoxy)tetrahydro-2-H-pyran(10B, 98.1 g, 0.383 mol) was then added to the solution at such a ratethat the temperature in the reaction mixture did not rise above -65°.The solution was allowed to warm slowly to RT and stirred for 14 h. Thevolume of the solution was reduced to 300 mL by a stream of dry N₂during the last few hours to facilitate the final workup. The reactionwas quenced with sat. NaCl (800 mL) and diluted with Et₂ O (800 mL). TheEt₂ O was removed and the aqueous layer extracted with hexane (500 mL).The Et₂ O and hexane layers were combined and dried (Na₂ SO₄). Thesolution was filtered and the solvent removed to give 124 g of crude redoil. Bulb to bulb distillation (in 1% aq. NEt₃ washed glassware) (210°bath temperature/0.3 mm) gave 95 g of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyratewhich was homogeneous by vpc and gave acceptable NMR and mass spectra.It was stored under N₂ in the refrigerator and was used without furtherpurification.

10D. 2-Benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol

A solution of ethyl2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate(10C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspensionof lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred indry THF (1 L) at such a rate to maintain a gentle reflux. After theaddition was complete the mixture was refluxed for 4 h. The reactionmixture was cooled and treated successively with H₂ O (23 mL), 15N NaOH(23 mL) and H₂ O (45 mL). The solid was removed by filtration and washedwith THF (200 mL). The organic layers were combined and concentrated byrotary evaporation to give2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g,92.0%) as a thick oil which was used without further purification.

10E. 2-Benzylamino-2-methyl-1,4-butanediol

The crude2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (10D,80.1 g, 0.273 mol) was dissolved in 3N HCl (128 mL). After 5 min themixture was washed with Et₂ O (200 mL). The aqueous solution wasconcentrated by rotary evaporation to give a thick oil which was cooledand basified with excess 50% NaOH. The oily amine which formed wasextracted with Et₂ O (3×200 mL). The Et₂ O extracts were combined andconcentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g(94%) of 2-benzylamino-2-methyl-1,4-butanediol as a pale yellow oil (bp168°-170°/0.35 mm) (C,H,N).

10F. 2-Amino-2-methyl-1,4-butanediol hydrochloride

2-Benzylamino-2-methyl-1,4-butanediol (10E, 31.08 g, 0.149 mol) wasdissolved in 95% EtOH (240 mL) containing concentrated HCl (21 mL, 0.25mol) and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over37 h at RT. The catalyst was then removed by filtration and the solventremoved by rotary evaporation (bath at 60°) to give 20.91 g of2-amino-2-methyl-1,4-butanediol hydrochloride (90.2%) as a clear, thick,colorless oil with acceptable NMR and mass spectra. It was used withoutfurther purification. This compound has been reported as its acetatesalt (G. Cardillo et al., Chem. Commun. 1308, 1982), but no data wasgiven. Attempts to duplicate the latter procedure were unsuccessful.

10G. 2-Methyl-2-((9-phenanthrenylmethyl)amino)-1,4-butanediolmethanesulfonate 3/10H₂ O

To a RB flask was added 2-amino-2-methyl-1,4-butanediol hydrochloride(10F) and an equal amount of sodium methoxide (MCB) and enough CH₃ OH toform a solution when warmed. The solvent was then removed by rotaryevaporation and after addition of 9-phenanthrene carbaldehyde (Aldrich)reaction run following the normal reductive amination procedure outlinedin 7G to give 2-methyl-2-((9-phenanthrenylmethyl)amino)-1,4-butanediolmethanesulfonate.3/10H₂ O mp 174°-176° (dec), (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 11

2-Isopropyl-2-((9-Phenanthrenylmethyl)amino)-1,3-propanediol

11A. 2-Isopropyl-2-nitro-1,3-propanediol

A solution of 2-methyl-1-nitropropane (38.7 g, 0.375 mol prepared by theprocedure of N. Kornblum, B. Taube, and H. Ungnade, J. Am. Chem. Soc.76, 3209 (1954) and NEt₃ (Eastman 3.79 g, 0.0375 mol) in CH₃ OH (50 mL)was added dropwise 37% aqueous formaldehyde solution (Mallinckrodt, 76.2g, 0.938 mol), at a rate such that the reaction mixture temperature didnot exceed 30°. After 72 h, the solution was concentrated under vacuumand the residue was dissolved in H₂ O (250 mL). The solution wascontinuously extracted for 1 h with CH₂ Cl₂ (1 L). The CH₂ Cl₂ solutionwas dried (MgSO₄), filtered, and concentrated to give 53.3 g (87%) of2-isopropyl-2-nitro-1,3-propanediol a waxy, white solid mp 67°-72° (lit.mp 87°-88°, B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34(1940). In our hands this procedure failed to give the desiredcompound).

11B. 2-Amino-2-isopropyl-1,3-propanediol acetate

Using the procedure in 7E, 2-isopropyl-2-nitro-1,3-propanediol gave a98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°.H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report thesynthesis of this compound as the free base (mp 70°-72°)).

11C. 2-Isopropyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediolmethanesulfonate

Using the reductive amination procedure described for 7G, 9-phenanthrenecarbaldehyde (Aldrich) and 2-amino-2-isopropyl-1,3-propanediol acetate(11B) gave 2-isopropyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediolmethanesulfonate mp 192°-194° (dec), (EtOH/Et₂ O), (C,H,N,S).

EXAMPLE 12

(1α,2β,3α)-2-((9-Phenanthrenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate

12A. (1α,2β,3α)-2-Amino-1,3-cyclohexanediol acetate

This compound was prepared by the method of F. Lichtenthaler (Ber. 96,851 (1963), mp 175°-177°, (C,H,N), (lit. 178°-179°, F. Lichtenthaler,Ber. 96, 845 (1963).

12B. (1α,2β,3α)-2-((9-Phenanthrenylmethyl)amino)-1,3-cyclohexanediolmethanesulfonate

Using the reductive amination procedure described for 7G,phenanthrene-9-carbaldehyde (Aldrich) and(1α,2β,3α)-2-amino-1,3-cyclohexanediol acetate (12B) gave(1α,2β,3α)-2-((9-phenanthrenylmethyl)amino)1,3-cyclohexanediolmethanesulfonate mp 222°-223°, (EtOH/Et₂ O), (C,H,N,S).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentalTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 13

Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test.Control and test animals are injected intraperitoneally with asuspension of ˜10⁶ viable P388/0 tumor cells on day 0. In each test,several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains 6 animals. The test compoundsare prepared either in physiologic saline containing 0.05% Tween 80 ordistilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P388/0 testing are summarized in Table I below.

                  TABLE I                                                         ______________________________________                                        P388/0 SCREENING RESULTS                                                                           T/C × 100%                                         Compound of                                                                            Optimal Dose                                                                              (Excluding 30 Day)                                       Example No.                                                                            (mg/kg)     Survivors      LD.sub.20.sup.A                           ______________________________________                                        1        144         +170           144                                       2B       175         +133           358                                       6B       250         +120           225                                       7G       100         +150            90                                       4        110         +120           150                                       10G      180         +195           180                                       ______________________________________                                         .sup.A Values in parentheses are the highest nontoxic dose where the          LD.sub.20 was not determined.                                            

EXAMPLE 14

Herpes simplex 1/vero Test

Antiviral testing against Herpes simplex 1/vero was done using plaqueinhibition methods as outlined in P. Collins and D. J. Bauer, Proc. N.Y.Acad. Sci. 284, 49 (1977) and by plaque reduction methods as outlined inP. Collins and D. J. Bauer, J. Antimicrobial Chemotherapy 3, SupplementA, 73, (1977). The column headings labeled Score, Toxicity, and Zone ofInhibition refer to the plaque inhibition screen while the IC₅₀ headingto the plaque reduction screen.

                  TABLE V                                                         ______________________________________                                        Results of Antiviral Screening Against Herpes simplex 1/vero                  Compound of               Zone of                                             Example No.                                                                            Score.sup.A                                                                           Toxicity Inhibition.sup.B                                                                       IC.sub.50.sup.B                            ______________________________________                                        1        -3      Y                                                            2B       -3      Y                 17.25 (ST at 25)                           6B       -4      Y                 20 (T)                                     7G       -4      Y                 3.6                                        8C       -2      Y        32 (ST at 20)                                       3D       -2      Y        32 (ST at 20)                                       9D       -4      Y        35 (T25)                                            ______________________________________                                         .sup.A Score Code:                                                            0 = no inhibition                                                             -1 = 1-25% inhibition                                                         -2 = 26-50% inhibition                                                        -3 = 51-75% inhibition                                                        -4 = 76-100% inhibition                                                       .sup.B ST = slight toxicity, T = toxic, VT = very toxic                  

Antibacterial Screening

Antibacterial testing against Mycoplasma smegmatis (S3264) was done withslight modifications using standard agar dilution assays as outlined inManual of Clinical Microbiology, Second Ed., E. H. Lennette, E. H.Spaulding and J. P. Truant Eds., American Society for Microbiology,Washington, DC, 1974.

EXAMPLE 15

Mycoplasma smegmatis Test

                  TABLE VI                                                        ______________________________________                                        Results of Antibacterial Screening Against                                    Mycoplasma smegmatis (S3264)                                                         Compound MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1        ≦5                                                     ______________________________________                                    

EXAMPLE 16

Candida albicans Testing

Antifungal testing against Candida albicans (CN1863) was done withslight modifications using a combination of broth and agar dilutionassays as outlined in Laboratory Handbook of Medical Mycology, Chapter6, pages 441-446, M. R. McGinnis, Academic Press, New York, NY, 1980.

                  TABLE VIII                                                      ______________________________________                                        Results of Antifungal Screening Against                                       Candida albicans (CN1863)                                                            Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1        >50                                                           ______________________________________                                         Medium: Wellcotest ™ sensitivity test agar plus 7% lysed horse blood. 

EXAMPLE 17

Nippostrongylus brasiliensis Testing

Anthelmintic testing against Nippostrongylus brasiliensis was done usingmethods as outlined in D. C. Jenkins, R. Armitage, and T. S. Carrington,Zetschrift fur Parasitenkunde 63, 261-269 (1980).

                  TABLE X                                                         ______________________________________                                        Results of Anthelmintic Screening Against Nippostrongylus                     brasiliensis (Immature - free living stages)                                         Compound of                                                                            MIC                                                                  Example No.                                                                            (mg/L)                                                        ______________________________________                                               1        ≧50                                                    ______________________________________                                    

EXAMPLE 18

Eimeria tenella Testing

Antiprotozoal testing against Eimeria tenella was done using methodsoutlined in V. S. Latter and D. Wilson, Parasitology 79, 169 (1979).

                  TABLE XI                                                        ______________________________________                                        Results of Antiprotozoal Screening Against                                    Eimeria tenella (in vitro)                                                    Compound of      Dose                                                         Example No.      (mg/L)  Result.sup.A                                         ______________________________________                                        1                5       -4                                                   ______________________________________                                         .sup.A Screen Code                                                            0 = no inhibition                                                             -1 = 1-25% inhibition                                                         -2 = 26-50% inhibition                                                        -3 = 51-75% inhibition                                                        -4 = 76-100% inhibition                                                  

EXAMPLE 19

LD₅₀ Tests

                  TABLE XIII                                                      ______________________________________                                        LD.sub.50 Values for Selected Compounds                                       (IP single dose - CD.sub.1 Male Mouse)                                        Compound of    LD.sub.50                                                      Example No.    (mg/kg)                                                        ______________________________________                                        1              160                                                            ______________________________________                                    

EXAMPLE 20

Formulation Examples A. TABLET

Compound of Formula I--500.0 mg

Pregelatinized Corn Starch--60.0 mg

Sodium Starch Glycolate--36.0 mg

Magnesium Stearate--4.0 mg

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

B. TABLET

Compound of formula (I)--500.0 mg

Corn Starch--70.0 mg

Lactose--83.8 mg

Magnesium Stearate--4.2 mg

Polyvinylpyrrolidone--14.0 mg

Stearic Acid--28.0 mg

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in purified water anddenatured alcohol to form granules. The granules are dried and mixedwith the powdered stearic acid and magnesium stearate. The formulationis then compressed into tablets weighing approximately 700 mg each.

C. CAPSULES

Compound of formula (I)--500.0 mg

Corn Starch--50.0 mg

Magnesium Stearate--3.0 mg

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

D. SYRUP

Compound of formula (I)--250.0 mg

Ethanol--250.0 mg

Glycerin--500.0 mg

Sucrose--3,500.0 mg

Flavoring Agent--q.s.

Coloring Agent--q.s.

Preserving Agent--0.1%

Purified Water--q.s. to 5.0 mL

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecoloring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

E. IV INJECTION

Compound of formula (I)--5.0 mg

Glycerin--q.s. for isotonicity

Preservative--0.1%

Hydrochloric Acid or--as needed for

Sodium Hydroxide--pH adjustment

Water for Injection--q.s. to 1 mL

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A pharmaceutical formulation containing acompound of formula (I)

    ArCH.sub.2 R.sup.1 (I)

or a monomethyl or monoethyl ether thereof, the compound of formula (I)including its ethers containing no more than 30 carbon atoms in total);ethers, esters thereof; acid addition salts thereof; wherein Ar is aphenanthrene ring optionally substituted by one or two substituents. Thesubstituents will contain not more than four carbon atoms in total whentaken together being the same or different and are selected fromhalogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substitutedby hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² isC₁₋₂ alkoxy; or the phenanthrene ring is optionally substituted by agroup NR³ R⁴ containing not more than 5 carbon atoms wherein R³ and R⁴are the same or different and each is a C₁₋₃ alkyl group; R¹ containsnot more than eight carbon atoms and is a group ##STR11## wherein m is 0or 1; R⁵ is hydrogen; R⁶ and R⁷ are the same or different and each ishydrogen or C₁₋₃ alkyl optionally substituted by hydroxy (proving thatat least one hydroxy group is present); R⁸ and R⁹ are the same ordifferent and each is hydrogen or C₁₋₃ alkyl; ##STR12## is a five- orsix-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl orhydroxymethyl; R¹¹, R¹² and R¹³ are the same or different and each ishydrogen or methyl; R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethylwith a pharmaceutically acceptable carrier in the form of a tablet,capsule, syrup, or a solution for injection excluding2-methyl-2-((9-phenanthrylmethyl)amino)-1,3-propanediol and2-methyl-2-((2-phenanthrylmethyl)amino)-1,3-propanediol.
 2. The methodof reducing the cells of a suceptible tumor which comprises contactingsaid susceptible tumor cells with the compound or salt of theformulation of claim
 1. 3. A method of claim 2 for a compound of formula(I) wherein Ar is 9-phenanthrenyl, ##STR13## R¹ is ##STR14## wherein mis 0; R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl; or a monomethyl or monoethylether thereof containing no more than 28 carbon atoms in total; acidaddition salts thereof.
 4. A method of claim 3 wherein R¹⁶ is CH₂ OH orCH(CH₃)OH and R¹⁷ is hydrogen, methyl, ethyl or CH₂ OH; acid additionsalts thereof.
 5. A method of claim 4 wherein R¹ is a diol of thestructure ##STR15## wherein R¹⁹ is hydrogen or methyl and R²⁰ ishydrogen, methyl or ethyl; acid addition salts thereof.
 6. A method ofclaim 5 wherein R²⁰ is methyl; acid addition salts thereof.
 7. A methodof claim 2 wherein the compound of formula (I) is a methanesulfonic,hydrochloric, ethanesulfonic, lactic, citric or isethionic acid additionsalt.
 8. A method of claim 2 wherein a compound of formula (I) isselected from2-Methyl-2-((4-phenanthrenylmethyl)amino)-1,3-propanediol,2-Methyl-2-((3-phenanthrenylmethyl)amino)-1,3-propanediol,(+-)(2R*,3S*)-2-((9-Phenanthrenylmethyl)amino)-2-methyl-1,3-butanediol,2-Ethoxymethyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol,2-(((10-Ethoxy-9-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol,3-Methoxy-2-methyl-2-((9-phenanthrenylmethyl)amino)-1-propanol,2-(((9-Ethoxy-1-phenanthrenyl)methyl)amino)-2-methyl-1,3-propanediol,2-Methyl-2-((9-phenanthrenylmethyl)amino)-1,4-butanediol,2-Isopropyl-2-((9-phenanthrenylmethyl)amino)-1,3-propanediol(1α,2β,3α)-2-((9-Phenanthrenylmethyl)amino)-1,3-cyclohexanediol; acidaddition salts thereof.
 9. A method of claim 8 wherein the compound offormula (I) is a methanesulfonic, hydrochloric, ethanesulfonic, lactic,citric or isethionic acid addition salt.